Chemotherapeutic agents current used for antitumor therapy are selected for their toxicity towards rapidly proliferating cells. Most of them cause undesirable systemic effects such as cardiac or renal toxicity, marrow aplasia, alopecia, nausea and vomiting. During the last few years, many authors have tried to eliminate these side effects by increasing the availability of the drug to the tumour site. Enzymes, radioisotopes, DNA, toxins, various macromolecules, and antibodies against fibrin or against tumour-specific surface antigens were bound to drugs in an attempt to increase the selectivity of the chemotherapeutic agents, or to decrease their toxic effects on normal cells (Rubens R. D., Lancet, 1, 1974, pp. 498-499; Gregoriadis G. et al., Res. Commun. Chem. Pathol. Pharm., 10, 1977, pp. 351-362).
The targeting of drugs to a tumour by antibodies to surface antigens may have considerable implications by increasing the therapeutic index.
It is recognized that the ideal antineoplastic drug would destroy cancer cells without adverse effects or toxicities on normal cells, but no such drug exists. However, despite the narrow therapeutic index of many drugs, treatment and even cure are possible in some patients.
Dactinomycin, doxorubicin and daunorubicin are all given rapidly intravenously and all cause tissue necrosis if extravasation occurs. When doxorubicin and daunorubicin are given rapidly intravenously, there is rapid dispersement throughout tissues and plasma. The .notident.t1/2 is 30 min, with detectable plasma levels of doxorubicin up to 15 h. Both doxorubicin and daunorubicin are extensively metabolized by the liver, yielding active and inactive metabolites.
Dactinomycin, doxorubicin and daunorubicin have limited antitumor activity. Dactinomycin is effective in testicular carcinoma and sarcomas. Daunorubicin is effective in treating acute leukemia. In contrast, doxorubicin is one of the most active antineoplastic ever identified. In fact it is used to treat acute leukemia, Hodgkin's disease and non-Hodgkin's lymphomas, small cell and non-small cell lung cancer, cancers of the breast, ovaries, stomach, thyroid, and bladder, osteogenic and soft tissue sarcomas, and malignant melanoma. The side effects include nauseas, vomiting, alopecia, myelosuppression, and dose-dependent cardiotoxicity (&gt;550 mg/m.sup.2).
Relyveld, U.S. Pat. No. 4,625,019, describes an autopolymerized antitumor agent, that is, daunorubicin is brought in contact with a bifunctional crosslinking agent, such as glutaraldehyde. A form of polymeric product is obtained, which is insoluble in aqueous media but which, on being resuspended in an aqueous medium in the absence of glutaraldehyde, gradually releases the antitumor agent in a soluble form. This method mainly consist of mixing together daunorubicin, an antibody and glutaraldehyde, which can combine in three different ways. The conjugates obtained can be any of the followings:
1-33%: Antibody-glutaraldehyde-Daunorubicin PA0 2-33%: Antibody-glutaraldehyde-Antibody PA0 3-33%: Daunorubicin-glutaraldehyde-Daunorubicin
and which only the Antibody-glutaraldehyde-Daunorubicin conjugate is active. Furthermore, these three possible conjugates can be linked together by the excess glutaraldehyde in solution to form an agglomerate, which makes it difficult to isolate the active conjugate. This is the reason why we refer to an autopolymerized antitumor agent in this patent.
This method is not readily reproducible and give an unstable conjugate product. Unfortunately, this autopolymerized antitumor agent has the disadvantage of being insoluble in water and thus looses its specific activity against tumor cells. This insoluble product can not be used intravenously for a systemic treatment since it is taken up by phagocytic cells such as monocytes, marcrophage or cells. This product is not very stable and do not have a very long shelf life.
The problems posed by the administration of antitumor agents or cytostatic agents are made particularly difficult by the nature of the illness and very high toxicity of the active products.
It would be highly desirable if the efficiency of the use of antitumor agents could be improved so as to allow their gradual release in the organism, while clearly improving their efficiency and the patient's comfort. It would also be highly desirable, if there could be such an antitumor agent which would be easily produce, substantially pure, which would also not have a tendency to polymerized and hence have a long shelf life.